Research focuses on neuroendocrine mechanisms of adaptation to stress, with emphasis on the regulation of the hypothalamic pituitary adrenal (HPA) axis. Previous studies of this laboratory demonstrated that repeated stress is associated with either desensitized or maintained ACTH responses to an homotypic stimulus but invariable enhanced responses to a heterotypical stress. Extension of these studies showed similar facilitation of the HPA axis activity 10 days after a single stress exposure. To study the mechanism of these responses, in situ hybridization studies with intronic probes were used to study CRH and VP transcription in the PVN. It was shown that preservation of ACTH responses to an homotypic repeated stimulus correlates with increased CRH expression, whereas hyperresponsiveness to a heterotypical superimposed stress correlates with increased VP expression. In presence of increased glucocorticoids, the increase in CRH transcription precedes that of VP in PVN neurons. The molecular mechanisms of the differential regulation of CRH and VP is under current investigation. Experiments using CRH antagonists showed that in addition of stimulating ACTH secretion in the pituitary, CRH acts upon brain CRH receptors to modulate HPA axis activity. CRH excerts a positive feedback in the CRH neuron while decreasing plasma ACTH. However, adrenocortical activity is enhanced, probably through sympathoadrenal stimulation. Studies in a mouse model of congenital adrenal hyperplasia (CAH), the 21-hydroxylase (21-OH) deficient mouse, showed that lack of glucocorticoids during fetal life causes hyperactivity of the HPA axis in the newborn, which cannot be prevented by prenatal dexamethasone treatment. This suggests that the current approach of glucocorticoid administration for prenatal treatment in humans is not the choice for prevention of hyperandrogenism. The consequences of fetal glucocorticoid deficiency on the setpoint of gluocorticoid feedback are under investigation. This mouse model was also used to demonstrate the feasibility of gene therapy for CAH. Intraadrenal injection of a replication deficient adenovirus vector containing the human cytochrome P45021-OH gene increased plasma corticosterone levels and restored adrenocortical structure in 21-OH deficient mice for about two weeks. Current efforts focus on the development of improved viral vectors to increase duration and efficiency of gene transfer.